Pyrazoline compounds compositions and use

ABSTRACT

There are described compounds of formula I, ##STR1## in which Ar 1  and Ar 2 , which may be the same or different, each independently represent phenyl or pyridinyl, the phenyl or the pyridinyl each optionally being substituted by one or more of halogen; hydroxy; --COOR 12  ; trihalomethyl; alkoxy C1 to 6; alkyl C1 to 6; --NR 1  R 2  ; alkoxy C1 to 6 substituted by --NR 1  R 2  or by phenyl; or alkyl C1 to 6 substituted by --NR 1  R 2  or by --COOR 12  ; 
     R 1  and R 2 , which may be the same or different, each independently represent hydrogen or alkyl C1 to 6, 
     R 3  represents hydrogen, alkyl C1 to 6, alkanoyl C1 to 6, benzoyl, --COOR 8 , or --CONHR 11 , 
     R 4 , R 5 , R 6  and R 7 , which may be the same or different each independently represent hydrogen, alkyl C1 to 6 or phenyl, 
     R 8  represents alkyl C1 to 6 or aryl, 
     R 11  represents alkyl C1 to 6 or aryl, 
     R 12  represents hydrogen or alkyl C1 to 6, and pharmaceutically acceptable derivatives thereof. 
     There are also described compositions containing the compounds and methods for their preparation. 
     The compounds are indicated for use as pharmaceutical, eg antiinflammatory agents.

This invention relates to new compounds, processes for their preparationand compositions containing them.

According to our invention we provide the compounds of formula I,##STR2## in which Ar₁ and Ar₂, which may be the same or different, eachindependently represent phenyl or pyridinyl, the phenyl or the pyridinyleach optionally being substituted by one or more of halogen; hydroxy;--COOR₁₂ ; trihalomethyl; alkoxy C1 to 6; alkyl C1 to 6; --NR₁ R₂ ;alkoxy C1 to 6 substituted by --NR₁ R₂ or by phenyl; or alkyl C1 to 6substituted by --NR₁ R₂ or by --COOR₁₂ ;

R₁ and R₂, which may be the same or different, each independentlyrepresent hydrogen or alkyl C1 to 6,

R₃ represents hydrogen, alkyl C₁ or 6, alkanoyl C1 to 6, benzoyl,--COOR₈, or --CONHR₁₁,

R₄, R₅, R₆ and R₇, which may be the same or different each independentlyrepresent hydrogen, alkyl C1 to 6 or phenyl,

R₈ represents alkyl C₁ to 6 or aryl,

R₁₁ represents alkyl C1 to 6 or aryl,

R₁₂ represents hydrogen or alkyl C1 to 6, and pharmaceuticallyacceptable derivatives thereof.

According to our invention we also provide a process for the preparationof the compounds of formula I, or a pharmaceutically acceptablederivative thereof which comprises

(a) producing a compound of formula I in which R₃ represents hydrogen oralkyl C1 to 6, by reacting a compound of formula II, ##STR3## in whichAr₁, R₄, R₅, R₆ and R₇ are as defined above,

and X is a good leaving group,

with a compound of formula III,

    R.sub.3 aNHAr.sub.2                                        III

in which R₃ a represents hydrogen or alkyl C1 to 6, and Ar₂ is asdefined above,

(b) producing a compound of formula I, in which R₃ represents alkanoylC1 to 6, benzoyl, or --COOR₈ by reacting a compound of formula I, inwhich R₃ represents hydrogen, with a compound of formula IV,

    R.sub.3 bY                                                 IV

in which R₃ b represents alkanoyl C1 to 6, benzoyl or --COOR₈ and Yrepresents a good leaving group,

(c) producing a compound of formula I, in which Ar₁ or Ar₂ bears ahydroxyl group, by selectively hydrogenating a corresponding compound offormula I, bearing a benzyloxy group,

(d) producing a compound of formula I, in which Ar₁ or Ar₂ bears analkoxy C1 to 6, or an alkoxy C1 to 6 substituted by --NR₁ R₂ or phenyl,by reacting a corresponding compound of formula I bearing a hydroxygroup, in the presence of a proton acceptor, with a compound of formulaV,

    R.sub.15 Y.sub.1                                           V

in which R₁₅ reprsents alkyl C1 to 6 or alkyl C1 to 6 appropriatelysubstituted by --NR₁ R₂ or phenyl and Y₁ represents a good leavinggroup, or

(e) producing a compound of formula I, in which R₃ represents CONHR₁₁,by reacting a corresponding compound of formula I in which R₃ representshydrogen, with a compound of formula VI,

    R.sub.11 N═C═O                                     VI

in which R₁₁ is as defined above,

and where desired or necessary converting the compound of formula I to apharmaceutically acceptable derivative thereof or vice versa.

In process (a) good leaving groups that X may represent include halogen,e.g. chlorine or bromine, arylsulphonyl, hydroxy and esters thereof,alkoxy, e.g. methoxy or ethoxy, dihalophosphoryl, e.g. dichloro- ordibromo-phosphoryl, and --NR₉ R₁₀, where R₉ and R₁₀ may eachindependently represent hydrogen or alkyl C1-6.

The compounds of formula II may, in certain cases, exist in tautomericforms. For example, when X represents hydroxy, the compound of formulaII may exist as a mixture of tautomers of formula A and formula B,##STR4##

The reaction may be carried out with or without a solvent. When thereaction is carried out using a solvent, the solvent is preferably inertto the conditions of the reaction, for example a polar aprotic solventsuch as 1,4-dioxan, acetonitrile or dimethylformamide. The reaction maybe carried out at a temperature of from about 25° to 150° C.

The reaction of process (b) may be carried out in a solvent which isinert to the conditions of the reaction, for example a halogenatedhydrocarbon, e.g. dichloromethane or dichloroethane; dimethylformamideor 1,4-dioxan. The reaction may be carried out at a temperature of from0° to 125° C. The reaction may be carried out in the presence of anadditional compound capable of accepting protons, eg a base, such astriethylamine or potassium carbonate.

Good leaving groups that Y may represent include halide, particularlychloride, and alkanoylate.

The selective hydrogenation of process (c) may be carried out usinghydrogen in the presence of a suitable catalyst, eg palladium oncharcoal. When hydrogen gas is used, the reaction is preferably carriedout at a pressure of 1 to 5 atmospheres at a temperature of from about0° to 100° C. in a solvent which is inert to the conditions of thereaction, eg ethanol or acetic acid.

In process (d), suitable proton acceptors include bases, for examplemetal alkoxides, eg potassium t-butoxide, metal carbonates, eg potassiumcarbonate, and trialkylamines, eg triethylamine. The reaction ispreferably carried out in a solvent which is inert to the reactionconditions. Polar solvents are particularly preferred, egdimethylformamide, 1,4 dioxan, tetrahydrofuran andN-methylpyrrolidinone. The reaction may be carried out at a temperatureof from about 0° to 150° C. Leaving groups that Y₁ may represent includethose described above for Y; chloride is particularly preferred.

The reaction of process (e) may be carried out in a solvent which isinert to the reaction conditions, eg a polar aprotic solvent. Suitablesolvents include tetrahydrofuran, 1,4-dioxan and dimethylformamide. Thereaction is preferably carried out at a temperature of from about 0° to100° C.

Compounds of formula II, in which R₄ and R₅ each represent alkyl C1 to 6or phenyl, X represents --OH, and Ar₁, Ar₂, R₃, R₆ and R₇ are as definedabove, may be prepared by reacting a compound of formula VII,

    Ar.sub.1 NHNH.sub.2                                        VII

in which Ar₁ is as defined above, with a compound of formula VIII,##STR5## in which R₄ c and R₅ c each independently represent alkyl C1 to6 or phenyl, Y₂ and Y₃ each independently represent good leaving groups,and R₆ and R₇ are as defined above.

Good leaving groups that Y₂ and Y₃ may represent include those given forY and Y₁ above; chloride is a particularly preferred leaving group. Thereaction may be carried out in a solvent inert to the reactionconditions, eg in a halogenated hydrocarbon such as dichloromethane, ata temperature of from 0° to the reflux temperature of the solvent. Thereaction is preferably carried out in the presence of a proton acceptor,eg a base such as triethylamine.

The compounds of formulae III, IV, V, VI, VII, VIII and the remainingcompounds of formula II are either known, or may be made from knowncompounds using conventional techniques known per se.

The acid addition salts of the compounds of formula I may be prepared byreaction of the free-base with an appropriate acid. The acid additionsalts may be converted to the corresponding free-base by the action of astronger base.

The processes as described above may produce the compound of formula Ior a derivative thereof. It is also within the scope of this inventionto treat any derivative so produced to liberate the free compound offormula I, or to convert one derivative into another.

The compounds of formula I and the intermediates therefore may beisolated from their reaction mixtures using conventional techniques.

Pharmaceutically acceptable derivatives of the compounds of formula Iinclude pharmaceutically acceptable acid addition salts. Suitable saltsinclude salts of mineral acids, for example, hydrohalic acids, e.g.hydrochloric acid or hydrobromic acid, or organic acids, e.g. formic,acetic or lactic acids. The acid may be polybasic, for examplesulphuric, fumaric or citric acid. When the compound of formula Iincludes a group --COOR₁₂ or --COOR₈, pharmaceutically acceptablederivatives include pharmaceutically acceptable salts, esters andamides. Suitable salts include ammonium, alkali metal (eg sodium,potassium and lithium) and alkaline earth metal (eg calcium ormagnesium) salts, and salts with suitable organic bases, eg salts withhydroxylamine, lower alkylamines such as methylamine or ethylamine, withsubstituted lower alkylamines, eg hydroxy substituted alkylamines suchas tris(hydroxymethyl) methylamine, with simple monocyclic nitrogenheterocyclic compounds, eg piperidine or morpholine, with an amino acid,eg lysine, ornithine, arginine, or an N-alkyl, especially an N-methylderivative of any one thereof, or with an aminosugar, eg glucamine,N-methylglucamine or glucosamine. Suitable esters include simple loweralkyl esters, eg the ethyl ester, esters derived from alcoholscontaining basic groups, eg di-lower alkyl amino substituted alkanolssuch as the 2-(diethylamino)-ethyl ester, and acyloxy alkyl esters, eg alower acyloxy-lower alkyl ester such as the pivaloyloxymethyl ester. Thepharmaceutically acceptable acid addition salts of the basic esters, egthe hydrochloride, the hydrobromide, the maleate or the fumarate salts,may also be used. The esters may be made by conventional techniques, egesterification or transesterification. The amides may be, for example,unsubstituted or mono- or di- C1 to 6 alkyl or phenyl amides and may bemade by conventional techniques, eg reactin of an ester of thecorrespnding acid with ammonia or an appropriate amine.

Other pharmaceutically acceptable derivatives are compounds which willbe suitable bioprecursors (prodrugs) of the compounds of formula I andwill be readily apparent to those skilled in the art and may be madefrom the compounds of formula I using conventional processes known perse or by processes analogous to those described above.

The compounds of formula I, and pharmaceutically acceptable derivativesthereof, are useful because they possess pharmacological activity inanimals. In particular, the compounds are useful as anti-inflammatoryagents as indicated in the following assay systems:

(a) rat carrageenan induced oedema, Winter et al, Proc. Soc. Exp. Biol.111, 544 (1962),

(b) inhibition of lipoxygenase, in the presence of exogenous arichidonicacid and measuring enzymic products by High Performance LiquidChromatography, after the method of B A Jakschik et al, Biochemical andBiophysical Research Communications, 95 (1), 103, (1980),

(c) inhibition of prostaglandin synthetase, utilising bovine seminalvesical microsomes as the enzyme source, and C-14 labelled arachidonicacid as substrate. The products are separated by thin layerchromatography and measured by scintillation counting, after the methodof R W Egan, J L Humes, S A Kuehl, Biochemistry 17, 2230 (1978)

(d) topical treatment of ocular inflammation, European patentapplication 0022578A.

The compounds are indicated for use in the treatment or prophylaxis ofinflammatory conditions in mammals, including man. Conditions that maybe specifically mentioned are: rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, adjuvant arthritis andother arthritic conditions, inflamed joints;

eczema, psoriasis or other inflammatory skin conditions such as sunburn;

inflammatory eye conditions including conjunctivitis;

lung disorders in which inflammation is involved, eg bronchitis, pigeonfancier's disease and farmer's lung;

conditions of the gastrointestinal tract including aphthous ulcers,gingivitis, Crohn's disease (a condition of the small, and sometimesalso of the large intestine), atrophic gastritis and gastritisvarialoforme (conditions of the stomach), ulcerative colitis (acondition of the large intestine and sometimes the small intestine)coeliac disease (a condition of the small intestine), regional ileitis(a regional inflammatory condition of the terminal ileum), pepticulceration (a condition of the stomach and duodenum) and irritable bowelsyndrome;

pyresis, pain;

and other conditions associated with inflammation, particularly those inwhich lipoxygenase and cyclooxygenase products are a factor.

For the above mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general satisfactory results are obtainedwhen the compounds are administered at a daily dosage of from about 0.1mg to about 20 mg per kg of animal body weight, preferably given individed doses 1 to 4 times a day or in sustained release form. For manthe total daily dose is in the range of from 7.0 mg to 1,400 mg and unitdosage forms suitable for oral administration comprise from 2.0 mg to1,400 mg of the compound admixed with a solid or liquid pharmaceuticalcarrier or diluent.

The compounds of formula I, and pharmaceutically acceptable derivativesthereof, may be used on their own or in the form of appropriatemedicinal preparations for enteral, parenteral or topicaladministration. Thus the new compounds may be compounded with inorganicor organic, pharmaceutically acceptable adjuvants, diluents or carriers.Examples of such adjuvants, diluents and carriers are:- for tablets anddragees: lactose, starch, talc, stearic acid; for capsules: tartaricacid or lactose; for injectable solutions: water, alcohols, glycerin,vegetable oils; for suppositories: natural or hardened oils or waxes.

Compositions in a form suitable for oral, ie oesophageal administrationinclude tablets, capsules and dragees;

compositions in a form suitable for administration to the lung includeaerosols, particularly pressurised aerosols;

compositions in a form suitable for administration to the skin includecreams, eg oil-in-water emulsions or water-in-oil emulsion;

compositions in a form suitable for administration to the eye includedrops and ointments.

We prefer the composition to contain up to 50% and more preferably up to25% by weight of the compound of formula I, or of the pharmaceuticallyacceptable derivative thereof.

The compounds of formula I and pharmaceutically acceptable derivativesthereof have the advantage that they are less toxic, more efficacious,are longer acting, more selective, are more potent, produce less sideeffects or have other useful pharmacological properties, than compoundsof similar structure.

Groups that Ar₁ and Ar₂ may represent include phenyl, 2-, 3- and4-pyridyl.

When Ar₁ or Ar₂ represent a substituted phenyl, or a substituted 2-, 3-or 4-pyridinyl, Ar₁ or Ar₂ preferably bears one, two or threesubstituents, which may be the same or different, selected from halogen,eg fluorine, chlorine or bromine; hydroxy, trihalomethyl, egtrichloromethyl, and especially trifluoromethyl; alkoxy C1 to 6,particularly alkoxy C1 to 4, especially methoxy, ethoxy or propyloxy;alkyl C1 to 6, particularly alkyl C1 to 4, especially methyl, ethyl orpropyl; or --NR₁ R₂. Alkyl groups that R₁ or R₂ may each independentlyrepresent include methyl, ethyl, propyl and butyl. Particular groupsthat --NR₁ R₂ may represent are --N(CH₃)₂ and --N(CH₂ CH₃)₂.

Other substituents that Ar₁ or Ar₂ may bear include alkyl C1 to 6 inwhich the alkyl is substituted by --NR₁ R₂, eg methyl, ethyl or propylsubstituted by --N(CH₃)₂ or --N(CH₂ CH₃)₂. A particularly preferredsubstituent is --CH₂ N(CH₂ CH₃)₂.

Ar₁ or Ar₂ may be substituted by alkyl C1 to 6 in which the alkyl issubstituted by --COOR₁₂, wherein R₁₂ represents alkyl C1 to 6,preferably alkyl C1 to 4, eg methyl, ethyl or propyl. Typicalsubstituents that may be mentioned include --CH₂ CO₂ CH₃, --CH₂ CH₂ CO₂C₂ H₅, --CH₂ CH₂ CH₂ CO₂ C₂ H₅.

Ar₁ or Ar₂ may be substituted by alkoxy C1 to 6, in which the alkoxy issubstituted by NR₁ R₂. The alkyl group is preferably alkyl C1 to 4, egmethyl, ethyl or propyl. R₁ and R₂ preferably represent alkyl C1 to 4,eg methyl, ethyl or propyl. Substituents that may be particularlymentioned include --(CH₂)₂ N(CH₂ CH₃)₂.

Specific groups that Ar₁ and Ar₂ may represent include:

phenyl,

4-chlorophenyl,

4-methoxyphenyl,

4-dimethylaminophenyl,

3-trifluoromethylphenyl,

4-methylphenyl,

3-hydroxy-4-propylphenyl,

3,4-dichlorophenyl,

4-carboxyphenyl,

4-(diethylaminoethoxy)phenyl,

4-benzyloxyphenyl,

2-and 3-pyridinyl,

4-methyl-2-pyridinyl,

4-hydroxyphenyl,

4-diethylaminomethylphenyl and

4-(carboxymethyl)methylphenyl.

Preferred groups that Ar₁ may represent include phenyl or pyridinyl, thephenyl optionally being substituted by one or more of halogen,trihalomethyl or alkyl C1 to 6. A particularly preferred group isphenyl.

Preferred groups that Ar₂ may represent include phenyl or phenylsubstituted by alkoxy C1 to 6 or by alkoxy C1 to 6 substituted by --NR₁R₂ or phenyl. Where the phenyl is substituted, the substituent ispreferably in the 4-position.

When R₃ represents alkyl C1 to 6, R₃ may represent pentyl or hexyl andespecially methyl, ethyl, propyl or butyl.

When R₃ represent alkanoyl C1 to 6, R₃ may represent pentanoyl orhexanoyl and especially formyl, acetyl, propionyl or butanoyl.

We particularly prefer compounds in which R₃ represents hydrogen oralkyl C1 to 6.

Aryl groups that R₈ and R₁₁ may represent include monocyclic benzenoidaromatics, e.g. phenyl.

Compounds of formula I in which one or more of R₄, R₅, R₆ and R₇represent alkyl C1 to 6 that may be specifically mentioned include thosein which one or more of R₄, R₅, R₆ and R₇ contain up to and includingfour carbon atoms, for example when one or more of R₄, R₅, R₆ and R₇represent methyl, ethyl or propyl. Compounds that may be particularlymentioned are those in which R₄ and R₅ are identical and/or R₆ and R₇are identical, eg when R₄ and R₅ both represent methyl, or when R₆ andR₇ both represent methyl.

Particular mention may also be made of compounds in which only one ofthe groups R₄, R₅, R₆ or R₇ is phenyl. We particularly prefer compoundsin which only R₆ is phenyl.

We particularly prefer compounds in which either both R₄ and R₅ or bothR₆ and R₇ represent alkyl C1 to 6.

Certain of the compounds of formula I possess one or more chiral centresand the invention also provides the compounds in the form of theirindividual optical isomers or as racemic or other mixtures thereof.Certain of the compounds of formula I may also exist as stereoisomersand in these cases the invention provides all stereoisomeric forms. Thevarious isomers may be prepared and/or separated using conventionalprocesses known per se.

The invention is illustrated but in no way limited by the followingExamples, in which temperatures are in degrees Celsius.

EXAMPLE 1 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine

A mixture of 1-phenyl-[1H]-pyrazolidin-3-one (0.162 g), 4-methoxyaniline(0.37 g) and p-toluenesulphonic acid (0.17 g) was heated in an oil bathat 140° under a nitrogen atmosphere for 15 minutes. The reaction wascooled and the products dissolved in 1% sodium hydroxide solution anddiethyl ether. The organic phase was separated and washed with 1%hydrochloric acid solution, water and then dried over sodium sulphate.The organic phase was filtered and evaporated to a pale oil which ontrituration with pentane gave the title compound (0.1 g) m.p. 153°-4°.

Analysis: Found: C=71.91%, H=6.30%, N=15.74% C₁₆ H₁₇ N₃ O requiresC=71.91%, H=6.41%, N=15.73%

EXAMPLE 2 1-(3-Trifluoromethylphenyl)-4,5-dihydro-N-(4-methoxyphenyl)-1H-pyrazol-3-amine

A mixture of 1-(3-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazol-3-amine(0.23 g), 4-methoxyaniline (0.37 g) and p-toluenesulphonic acid (0.17 g)was heated in an oil bath at 140° under nitrogen for 15 minutes. Thereaction was cooled, dilute hydrochloric acid and ether added and theorganic phase separated, dried over sodium sulphate, filtered andevaporated to leave a yellow solid, which on trituration with pentanegave the colourless title compound (0.1 g) m.p. 127°-8°.

EXAMPLE 3 N-(4-Chlorophenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (a)3-Chloro-4,5-dihydro-1-phenyl-1H-pyrazole

1-Phenylpyrazolidin-3-one (8.1 g) was suspened in dry toluene (100 ml),followed by addition of phosphoryl chloride (7.0 ml) and the mixturestirred for 1 hour at 85° . When cool the toluene was decanted from thesolid and solvent removed in vacuo to give the sub-title compound, (6.9g), mp 92°-93°.

(b) N-(4-Chlorophenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine

3-Chloro-4,5-dihydro-1-phenylpyrazole (1.8 g) and 4-chloroaniline (3.8g) were fused under N₂ at 140° for 20 minutes. The melt was cooled andthe solid dissolved in CH₂ Cl₂, washed with 1% HCl (×3), water, dried(Na₂ SO₄), then absorbed into silica and column chromatographed usingfirst 1:1 petrol: ether and then ether to give the title product as ayellow powder (1.0 g), (37%), m.p. 144°-7°.

EXAMPLE 4N-(4,5-dihydro-1-phenyl-1H-pyrazol-3-yl)-N-(4-methoxyphenyl)acetamide

1.7M n-butyl lithium in hexane (7.0 ml) was added dropwise to a solutionof 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine (2.67 g)in tetrahydrofuran (150 ml) at -25° under N₂. After 40 minutes ethylacetate was added and the solution was allowed to reach roomtemperature. After being stirred for 2 hours, the solution wasevaporated to dryness and the residue chromatographed on silica geleluting with ethyl acetate in dichloromethane to give an oil whichcrystallised on trituration with ether. The solid was recrystallisedfrom ether and hexane to give the title compound (0.82 g) mp 83°-5°(dec).

Found: C=69.64%, H=6.12%, N=13.68%.

C₁₈ H₁₉ N₃ O₂ requires: C=69.90%, H=6.15%, N=13.59%.

EXAMPLE 5 EthylN-(4,5-dihydro-1-phenyl-1H-pyrazol-3-yl)-N-(3-pyridinyl)carbamate

Ethylchloroformate (0.75 ml) was added dropwise to a solution of4,5-dihydro-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine (1.66 g) andtriethylamine (2.85 ml) in tetrahydrofuran (150 ml) at -45° under N₂.The solution was allowed to warm to room temperature and stirred for 24hours. The solution was filtered, evaporated to dryness, and the residuechromatographed on silica gel eluting with ethyl acetate indichloromethane to give an oil which crystallised on triturating withether. The solid was recrystallised from ether and petrol to give thetitle compound (0.66 g) mp 110°-12° (dec).

Found: C=65.54%, H=5.93%, N=17.96%.

C₁₇ H₁₈ N₄ O₂ requires: C=65.80%, H=5.85%, N=18.06%.

EXAMPLE 6N-[4-(2-diethylaminoethoxy)phenyl]-N-[4,5-dihydro-1-phenyl-1H-pyrazol-3-yl]-N'-phenylurea

Phenylisocyanate (1.05 ml) was added dropwise to a solution ofN-[4-(2-diethylaminoethoxy)phenyl]-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine(2.4 g) in tetrahydrofuran (30 ml) and the solution heated to reflux for4 hours. After cooling the solvent was removed and water added to theresidue, which was then extracted with ether. The combined ether layerwas washed with water and dried. Solvent was removed to give a solidwhich was recrystallised from ethyl acetate and petroleum ether to givethe title compound (1.3 g) mp 140°-1°.

Found: C=71.35%, H=6.83%, N=14.84%.

C₂₈ H₃₃ N₅ O₂ requires: C=71.33%, H=7.06%, N=14.86%.

EXAMPLE 7 4,5-Dihydro-N-(4-hydroxyphenyl-1-phenyl-1H-pyrazol-3-amine

A suspension ofN-(4-benzyloxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (6.9 g) inethanol (350 ml) was hydrogenated at atmospheric pressure over 10%palladium on carbon until hydrogen uptake ceased. The mixture wasfiltered and the filtrate evaporated to small volume. The resultingprecipitate was collected, washed with ethanol and dried to give thetitle compound, (3.32 g) mp 211°-14° (dec).

Found: C=71.16%, H=5.99%, N=16.59%.

C₁₅ H₁₅ N₃ O requires: C=71.11%, H=5.97%, N=16.60%.

EXAMPLE 8N-[4-(2-diethylaminoethoxy)phenyl]-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine2E-butenedioate

Potassium carbonate (6.92 g),4,5-dihydro-N-(4-hydroxyphenyl)-1-phenyl-1H-pyrazol-3-amine (4.22 g) and2-diethylaminoethylchloride hydrochloride (2.95 g) in dimethylformamide(30 ml) were stirred together at room temperature for 25 hours. Thereaction mixture was then diluted with water and extracted with ethylacetate. The combined extracts were washed with water and dried. Solventwas removed to give an oil which was redissolved in ether and a solutionof fumaric acid (0.33 g) in ether added to give a precipitate. This wascollected and dried to give the title compound, (4.2 g) mp 54°-56°(dec).

Found: C=63.49%, H=6.72%, N=12.14%.

C₂₅ H₃₂ N₄ O₅ requires: C=64.10%, H=6.89%, N=11.86%.

EXAMPLE 9 4,4-Dimethyl-1-(2-pyridinyl)-3-pyrazolidinone

2-Pyridylhydrazine (10.9 g) in dichloromethane (120 ml) and drytriethylamine (28 ml) were chilled in an ice bath. -β-chloropivaloylchloride (15.5 g) in dichloromethane (20 ml) was added dropwise withstirring for 15 minutes and the mixture was refluxed for 3 hours. Whencool the triethylamine hydrochloride was filtered off and the filtrateevaporated to dryness and rinsed four times with the minimum quantity ofether to give the title compound (13.6 g) after recrystallisation fromcyclohexane mp 141°-144°.

EXAMPLE 10

The following compounds were prepared from the corresponding4,5-dihydro-1H-pyrazol-3-amine, using the method of Example 2:

(a)1-(3,4-Dichlorophenyl)-4,5-dihydro-N-(4-methoxyphenyl)-1H-pyrazol-3-amine,mp 142°-4°,

(b)4,5-Dihydro-5,5-dimethyl-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine, mp147°-9°,

(c)4,5-Dihydro-5,5-dimethyl-N-(4-dimethylaminophenyl)-1-phenyl-1H-pyrazol-3-amine,mp 166°-7°,

(d) 1-(3-Trifluoromethylphenyl)-4,5-dihydro-N-phenyl-1H-pyrazol-3-amine,mp 128°-9°,

(e) (±)-4,5-Dihydro-1,5,N-triphenyl-1H-pyrazol-3-amine, mp 172°-3°,

(f) (±)-4,5-Dihydro-1,5-diphenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine, mp168°-70°,

(g)1-(4-Chlorophenyl)-4,5-dihydro-N-(4-methylpyridin-2-yl)-1H-pyrazol-3-amine,mp 208°-10°,

(h) 1-(4-Chlorophenyl-4,5-dihydro-N-(3-pyridinyl)-1H-pyrazol-3-amine, mp234°-6°,

(i)1-(3-Trifluoromethylphenyl)-4,5-dihydro-N-(3-pyridinyl)-1H-pyrazol-3-amine,mp 235°-7° (dec),

(j) N-(4-Benzyloxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol -3-amine, mp187°-8°,

(k) 4-(4,5-Dihydro-1-phenyl-1H-pyrazol-3-yl)aminobenzoic acid, mp232°-5°,

(l) 4,5-Dihydro-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine, mp200°-202°,

(m) 4,5-Dihydro-N-(4-dimethylaminophenyl)-1-phenyl-1H- pyrazol-3-amine,mp 142°-3°,

(n)4,5-Dihydro-N-(4-methoxyphenyl)-1-(4-methylphenyl)-1H-pyrazol-3-amine,mp 163°-165°,

(o)1-(4-Chlorophenyl)-4,5-dihydro-N-(4-methoxyphenyl)-1H-pyrazol-3-amine,mp 145°-146°,

(p)N-[(4-Diethylaminomethyl)phenyl]-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine2E-butenedioate, mp 48°-52°,

(q) (±)-4,5-Dihydro-N-(4-methoxyphenyl)-5-methyl-1-phenyl-1H-pyrazol-3-amine, mp 47°-50°,

(r)4,5-Dihydro-N-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine, mp97°-100°,

(s) Methyl 4-[4,5-dihydro-1-phenyl-1H-pyrazol-3-yl]amino phenylacetate,mp 108°-109°,

(t) 4,5-Dihydro-1,N-diphenyl-1H-3-amine, mp 155°-6°.

EXAMPLE 11

The following compounds were prepared from the corresponding3-chloro-4,5-dihydro-1H-pyrazole, using the method of Example 3:

(a) 4,5-Dihydro-N-(4-methylphenyl)-1-phenyl-1H-pyrazol-3-amine, mp145°-9°,

(b) 4,5-Dihydro-N-methyl-1,N-diphenyl-1H-pyrazol-3-amine, mp 100°-102°,

(c)4,5-Dihydro-4,4-dimethyl-N-(4-dimethylaminophenyl)-1-phenyl-1H-pyrazol-3-amine,mp 155°-158°,

(d)4,5-Dihydro-N-(4-methoxyphenyl)-4,4-dimethyl-1-(2-pyridinyl)-1H-pyrazol-3-amine,mp 137°-9°,

(e) 4,5-Dihydro-N-(4-methoxyphenyl)-4,4-dimethyl-1H-pyrazol-3-amine, mp111°-112°,

(f) 4,5-Dihydro-N-(4-methoxyphenyl)-5,5-dimethyl-1-phenyl-1H-pyrazol-3-amine, mp 112°-14°,

(g)4,5-Dihydro-N-(3-hydroxy-4-propylphenyl)-1-phenyl-1H-pyrazol-3-amine, mp167°-70° (dec).

EXAMPLE 12

The following compound was prepared from the corresponding1,N-diaryl-4,5-dihydro-1H-pyrazol-3-amine using the method of Example 5:

(a) Ethyl[N-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl]-N-[4-methoxyphenyl]carbamate,mp 92°-94°.

EXAMPLE 13

The following compound was prepared from the corresponding1,N-diaryl-4,5-dihydro-1H-pyrazol-3-amine using the method of Example 6:

(a)N-[4,5-Dihydro-1-phenyl-1H-pyrazol-3-yl]-N-[3-pyridinyl]-N'-phenylurea,mp 163°-5°.

What we claim is:
 1. A compound of formula I, ##STR6## in which Ar₁ andAr₂, which may be the same or different, each independently representphenyl or pyridinyl, the phenyl or the pyridinyl each optionally beingsubstituted by one or more of halogen; hydroxy; COOR₁₂ ; trihalomethyl;alkoxy C1 to 6; alkyl C1 to 6; --NR₁ R₂ ; alkoxy C1 to 6 substituted byNR₁ R₂ or by phenyl; or alkyl C1 to 6 substituted by NR₁ R₂ or by--COOR₁₂ ;R₁ and R₂, which may be the same or different, eachindependently represent hydrogen or alkyl C1 to 6, R₃ represents--COOR₈, or --CONHR₁₁, R₄, R₅, R₆ and R₇, which may be the same ordifferent each independently represent hydrogen, alkyl C1 to 6 orphenyl, R₈ represents alkyl C1 to 6 or phenyl, R₁₁ represents alkyl C1to 6 or phenyl, R₁₂ represents hydrogen or alkyl C1 to 6, or apharmaceutically acceptable acid addition salt, ester, amide, or prodrugthereof.
 2. A compound according to claim 1, wherein Ar₁ representsphenyl or pyridinyl, the phenyl being optionally substituted by one ormore of halogen, trihalomethyl or alkyl C1 to
 6. 3. A compound accordingto claim 1, wherein Ar₂ represents phenyl, the phenyl optionally beingsubstituted by alkoxy C1 to 6 or by alkoxy C1 to 6 substituted by NR₁ R₂or phenyl.
 4. A compound according to claim 1, wherein either both R₄and R₅ or both R₆ and R₇ represent alkyl C1 to
 6. 5. EthylN-(4,5-dihydro-1-phenyl-1H-pyrazol-3-yl),N-(3-pyridinyl)carbamate,N-[4-(2-Diethylaminoethoxy)phenyl]-N-[4,5-dihydro-1-phenyl-1H-pyrazol-3-yl]-N'-phenylurea,EthylN-[(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl]-N-[4-methoxyphenyl]carbamate,orN-[4,5-Dihydro-1-phenyl-1H-pyrazol-3-yl]-N-[3-pyridinyl]-N'-phenylurea.6. A composition for treating an inflammatory condition comprising aneffective amount of a compound according to any one of the precedingclaims in admixture with a pharmaceutically acceptable adjuvant, diluentor carrier.
 7. A method of treatment of an inflammatory condition, whichcomprises administration of an effective amount of a compound accordingto claim 1 to a patient suffering from such a condition.